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ERC FUNDED PROJECTS

ProjectNeural mechanisms of body ownership and the projection of ownership onto artificial bodies

Researcher (PI)H. Henrik Ehrsson

Host Institution (HI)KAROLINSKA INSTITUTET

Call DetailsStarting Grant (StG), LS4, ERC-2007-StG

SummaryHow do we recognize that our limbs are part of our own body, and why do we feel that one’s self is located inside the body? These fundamental questions have been discussed in theology, philosophy and psychology for millennia. The aim of my ground-breaking research programme is to identify the neuronal mechanisms that produce the sense of ownership of the body, and the processes responsible for the feeling that the self is located inside the physical body. To solve these questions I will adopt an inter-disciplinary approach using state-of-the-art methods from the fields of imaging neuroscience, experimental psychology, computer science and robotics. My first hypothesis is that the mechanism for body ownership is the integration of information from different sensory modalities (vision, touch and muscle sense) in multi-sensory brain areas (ventral premotor and intraparietal cortex). My second hypothesis is that the sense of where you are located in the environment is mediated by allocentric spatial representations in medial temporal lobes. To test this, I will use perceptual illusions and virtual-reality techniques that allow me to manipulate body ownership and the perceived location of the self, in conjunction with non-invasive recordings of brain activity in healthy humans. Functional magnetic resonance imaging and electroencephalography will be used to identify the neuronal correlates of ownership and ‘in-body experiences’, while transcranial magnetic stimulation will be used to examine the causal relationship between neural activity and ownership. It is no overstatement to say that my pioneering work could define a new sub-field in cognitive neuroscience dealing with how the brain represents the self. These basic scientific discoveries will be used in new frontier applications. For example, the development of a prosthetic limb that feels just like a real limb, and a method of controlling humanoid robots by the illusion of ‘becoming the robot’.

How do we recognize that our limbs are part of our own body, and why do we feel that one’s self is located inside the body? These fundamental questions have been discussed in theology, philosophy and psychology for millennia. The aim of my ground-breaking research programme is to identify the neuronal mechanisms that produce the sense of ownership of the body, and the processes responsible for the feeling that the self is located inside the physical body. To solve these questions I will adopt an inter-disciplinary approach using state-of-the-art methods from the fields of imaging neuroscience, experimental psychology, computer science and robotics. My first hypothesis is that the mechanism for body ownership is the integration of information from different sensory modalities (vision, touch and muscle sense) in multi-sensory brain areas (ventral premotor and intraparietal cortex). My second hypothesis is that the sense of where you are located in the environment is mediated by allocentric spatial representations in medial temporal lobes. To test this, I will use perceptual illusions and virtual-reality techniques that allow me to manipulate body ownership and the perceived location of the self, in conjunction with non-invasive recordings of brain activity in healthy humans. Functional magnetic resonance imaging and electroencephalography will be used to identify the neuronal correlates of ownership and ‘in-body experiences’, while transcranial magnetic stimulation will be used to examine the causal relationship between neural activity and ownership. It is no overstatement to say that my pioneering work could define a new sub-field in cognitive neuroscience dealing with how the brain represents the self. These basic scientific discoveries will be used in new frontier applications. For example, the development of a prosthetic limb that feels just like a real limb, and a method of controlling humanoid robots by the illusion of ‘becoming the robot’.

SummaryThe core function of all brains is to compute the current state of the world, compare it to the desired state of the world and select motor programs that drive behavior minimizing any mismatch. The circuits underlying these functions are the key to understand brains in general, but so far they are completely unknown. Three problems have hindered progress: 1) The animal’s desired state of the world is rarely known. 2) Most studies in simple models have focused on sensory driven, reflex-like processes, and not considered self-initiated behavior. 3) The circuits underlying complex behaviors in vertebrates are widely distributed, containing millions of neurons. With this proposal I aim at overcoming these problems using insects, whose tiny brains solve the same basic problems as our brains but with 100,000 times fewer cells. Moreover, the central complex, a single conserved brain region consisting of only a few thousand neurons, is crucial for sensory integration, motor control and state-dependent modulation, essentially being a ‘brain in the brain’. To simplify the problem further I will focus on navigation behavior. Here, the desired and actual states of the world are equal to the desired and current headings of the animal, with mismatches resulting in compensatory steering. I have previously shown how the central complex encodes the animal’s current heading. Now I will use behavioral training to generate animals with highly defined desired headings, and correlate neural activity with the animal’s ‘intentions’ and actions - at the level of identified neurons. To establish the involved conserved core circuitry valid across insects I will compare species with distinct lifestyles. Secondly, I will reveal how these circuits have evolved to account for each species’ unique ecology. The proposed work will provide a coherent framework to study key concepts of fundamental brain functions in unprecedented detail - using a single, conserved, but flexible neural circuit.

The core function of all brains is to compute the current state of the world, compare it to the desired state of the world and select motor programs that drive behavior minimizing any mismatch. The circuits underlying these functions are the key to understand brains in general, but so far they are completely unknown. Three problems have hindered progress: 1) The animal’s desired state of the world is rarely known. 2) Most studies in simple models have focused on sensory driven, reflex-like processes, and not considered self-initiated behavior. 3) The circuits underlying complex behaviors in vertebrates are widely distributed, containing millions of neurons. With this proposal I aim at overcoming these problems using insects, whose tiny brains solve the same basic problems as our brains but with 100,000 times fewer cells. Moreover, the central complex, a single conserved brain region consisting of only a few thousand neurons, is crucial for sensory integration, motor control and state-dependent modulation, essentially being a ‘brain in the brain’. To simplify the problem further I will focus on navigation behavior. Here, the desired and actual states of the world are equal to the desired and current headings of the animal, with mismatches resulting in compensatory steering. I have previously shown how the central complex encodes the animal’s current heading. Now I will use behavioral training to generate animals with highly defined desired headings, and correlate neural activity with the animal’s ‘intentions’ and actions - at the level of identified neurons. To establish the involved conserved core circuitry valid across insects I will compare species with distinct lifestyles. Secondly, I will reveal how these circuits have evolved to account for each species’ unique ecology. The proposed work will provide a coherent framework to study key concepts of fundamental brain functions in unprecedented detail - using a single, conserved, but flexible neural circuit.

Max ERC Funding

1 500 000 €

Duration

Start date: 2017-01-01, End date: 2021-12-31

Project acronymCAAXPROCESSINGHUMDIS

ProjectCAAX Protein Processing in Human DIsease: From Cancer to Progeria

Researcher (PI)Martin Olof Bergö

Host Institution (HI)GOETEBORGS UNIVERSITET

Call DetailsStarting Grant (StG), LS6, ERC-2007-StG

SummaryMy objective is to understand the physiologic and medical importance of the posttranslational processing of CAAX proteins (e.g., K-RAS and prelamin A) and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and progeria. CAAX proteins undergo three posttranslational processing steps at a carboxyl-terminal CAAX motif. These processing steps, which are mediated by four different enzymes (FTase, GGTase-I, RCE1, and ICMT), increase the hydrophobicity of the carboxyl terminus of the protein and thereby facilitate interactions with membrane surfaces. Somatic mutations in K-RAS deregulate cell growth and are etiologically involved in the pathogenesis of many forms of cancer. A mutation in prelamin A causes Hutchinson-Gilford progeria syndrome—a pediatric progeroid syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., the plasma membrane and the nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif. My Specific Aims are: (1) To define the suitability of the CAAX processing enzymes as therapeutic targets in the treatment of K-RAS-induced lung cancer and leukemia; and (2) To test the hypothesis that inactivation of FTase or ICMT will ameliorate disease phenotypes of progeria. I have developed genetic strategies to produce lung cancer or leukemia in mice by activating an oncogenic K-RAS and simultaneously inactivating different CAAX processing enzymes. I will also inactivate several CAAX processing enzymes in mice with progeria—both before the emergence of phenotypes and after the development of advanced disease phenotypes. These experiments should reveal whether the absence of the different CAAX processing enzymes affects the onset, progression, or regression of cancer and progeria.

My objective is to understand the physiologic and medical importance of the posttranslational processing of CAAX proteins (e.g., K-RAS and prelamin A) and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and progeria. CAAX proteins undergo three posttranslational processing steps at a carboxyl-terminal CAAX motif. These processing steps, which are mediated by four different enzymes (FTase, GGTase-I, RCE1, and ICMT), increase the hydrophobicity of the carboxyl terminus of the protein and thereby facilitate interactions with membrane surfaces. Somatic mutations in K-RAS deregulate cell growth and are etiologically involved in the pathogenesis of many forms of cancer. A mutation in prelamin A causes Hutchinson-Gilford progeria syndrome—a pediatric progeroid syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., the plasma membrane and the nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif. My Specific Aims are: (1) To define the suitability of the CAAX processing enzymes as therapeutic targets in the treatment of K-RAS-induced lung cancer and leukemia; and (2) To test the hypothesis that inactivation of FTase or ICMT will ameliorate disease phenotypes of progeria. I have developed genetic strategies to produce lung cancer or leukemia in mice by activating an oncogenic K-RAS and simultaneously inactivating different CAAX processing enzymes. I will also inactivate several CAAX processing enzymes in mice with progeria—both before the emergence of phenotypes and after the development of advanced disease phenotypes. These experiments should reveal whether the absence of the different CAAX processing enzymes affects the onset, progression, or regression of cancer and progeria.

Max ERC Funding

1 689 600 €

Duration

Start date: 2008-06-01, End date: 2013-05-31

Project acronymCaBiS

ProjectChemistry and Biology in Synergy - Studies of hydrogenases using a combination of synthetic chemistry and biological tools

Researcher (PI)Gustav Oskar BERGGREN

Host Institution (HI)UPPSALA UNIVERSITET

Call DetailsStarting Grant (StG), LS1, ERC-2016-STG

SummaryMy proposal aims to take advantage of my ground-breaking finding that it is possible to mature, or activate, the [FeFe] hydrogenase enzyme (HydA) using synthetic mimics of its catalytic [2Fe] cofactor. (Berggren et al, Nature, 2013) We will now explore the chemistry and (bio-)technological potential of the enzyme using an interdisciplinary approach ranging from in vivo biochemical studies all the way to synthetic model chemistry. Hydrogenases catalyse the interconversion between protons and H2 with remarkable efficiency. Consequently, they are intensively studied as alternatives to Pt-catalysts for these reactions, and are arguably of high (bio-) technological importance in the light of a future “hydrogen society”.
The project involves the preparation of novel “artificial” hydrogenases with the primary aim of designing spectroscopic model systems via modification(s) of the organometallic [2Fe] subsite. In parallel we will prepare in vitro loaded forms of the maturase HydF and study its interaction with apo-HydA in order to further elucidate the maturation process of HydA. Moreover we will develop the techniques necessary for in vivo application of the artificial activation concept, thereby paving the way for a multitude of studies including the reactivity of artificial hydrogenases inside a living cell, but also e.g. gain-of-function studies in combination with metabolomics and proteomics. Inspired by our work on the artificial maturation system we will also draw from our knowledge of Nature’s [FeS] cluster proteins in order to prepare a novel class of “miniaturized hydrogenases” combining synthetic [4Fe4S] binding oligopeptides with [2Fe] cofactor model compounds.
Our interdisciplinary approach is particularly appealing as it not only provides further insight into hydrogenase chemistry and the maturation of metalloproteins, but also involves the development of novel tools and concepts applicable to the wider field of bioinorganic chemistry.

My proposal aims to take advantage of my ground-breaking finding that it is possible to mature, or activate, the [FeFe] hydrogenase enzyme (HydA) using synthetic mimics of its catalytic [2Fe] cofactor. (Berggren et al, Nature, 2013) We will now explore the chemistry and (bio-)technological potential of the enzyme using an interdisciplinary approach ranging from in vivo biochemical studies all the way to synthetic model chemistry. Hydrogenases catalyse the interconversion between protons and H2 with remarkable efficiency. Consequently, they are intensively studied as alternatives to Pt-catalysts for these reactions, and are arguably of high (bio-) technological importance in the light of a future “hydrogen society”.
The project involves the preparation of novel “artificial” hydrogenases with the primary aim of designing spectroscopic model systems via modification(s) of the organometallic [2Fe] subsite. In parallel we will prepare in vitro loaded forms of the maturase HydF and study its interaction with apo-HydA in order to further elucidate the maturation process of HydA. Moreover we will develop the techniques necessary for in vivo application of the artificial activation concept, thereby paving the way for a multitude of studies including the reactivity of artificial hydrogenases inside a living cell, but also e.g. gain-of-function studies in combination with metabolomics and proteomics. Inspired by our work on the artificial maturation system we will also draw from our knowledge of Nature’s [FeS] cluster proteins in order to prepare a novel class of “miniaturized hydrogenases” combining synthetic [4Fe4S] binding oligopeptides with [2Fe] cofactor model compounds.
Our interdisciplinary approach is particularly appealing as it not only provides further insight into hydrogenase chemistry and the maturation of metalloproteins, but also involves the development of novel tools and concepts applicable to the wider field of bioinorganic chemistry.

Max ERC Funding

1 494 880 €

Duration

Start date: 2017-02-01, End date: 2022-01-31

Project acronymCC-MEM

ProjectCoordination and Composability: The Keys to Efficient Memory System Design

Researcher (PI)David BLACK-SCHAFFER

Host Institution (HI)UPPSALA UNIVERSITET

Call DetailsStarting Grant (StG), PE6, ERC-2016-STG

SummaryComputer systems today are power limited. As a result, efficiency gains can be translated into performance. Over the past decade we have been so effective at making computation more efficient that we are now at the point where we spend as much energy moving data (from memory to cache to processor) as we do computing the results. And this trend is only becoming worse as we demand more bandwidth for more powerful processors. To improve performance we need to revisit the way we design memory systems from an energy-first perspective, both at the hardware level and by coordinating data movement between hardware and software.
CC-MEM will address memory system efficiency by redesigning low-level hardware and high-level hardware/software integration for energy efficiency. The key novelty is in developing a framework for creating efficient memory systems. This framework will enable researchers and designers to compose solutions to different memory system problems (through a shared exchange of metadata) and coordinate them towards high-level system efficiency goals (through a shared policy framework). Central to this framework is a bilateral exchange of metadata and policy between hardware and software components. This novel communication will open new challenges and opportunities for fine-grained optimizations, system-level efficiency metrics, and more effective divisions of responsibility between hardware and software components.
CC-MEM will change how researchers and designers approach memory system design from today’s ad hoc development of local solutions to one wherein disparate components can be integrated (composed) and driven (coordinated) by system-level metrics. As a result, we will be able to more intelligently manage data, leading to dramatically lower memory system energy and increased performance, and open new possibilities for hardware and software optimizations.

Computer systems today are power limited. As a result, efficiency gains can be translated into performance. Over the past decade we have been so effective at making computation more efficient that we are now at the point where we spend as much energy moving data (from memory to cache to processor) as we do computing the results. And this trend is only becoming worse as we demand more bandwidth for more powerful processors. To improve performance we need to revisit the way we design memory systems from an energy-first perspective, both at the hardware level and by coordinating data movement between hardware and software.
CC-MEM will address memory system efficiency by redesigning low-level hardware and high-level hardware/software integration for energy efficiency. The key novelty is in developing a framework for creating efficient memory systems. This framework will enable researchers and designers to compose solutions to different memory system problems (through a shared exchange of metadata) and coordinate them towards high-level system efficiency goals (through a shared policy framework). Central to this framework is a bilateral exchange of metadata and policy between hardware and software components. This novel communication will open new challenges and opportunities for fine-grained optimizations, system-level efficiency metrics, and more effective divisions of responsibility between hardware and software components.
CC-MEM will change how researchers and designers approach memory system design from today’s ad hoc development of local solutions to one wherein disparate components can be integrated (composed) and driven (coordinated) by system-level metrics. As a result, we will be able to more intelligently manage data, leading to dramatically lower memory system energy and increased performance, and open new possibilities for hardware and software optimizations.

SummaryThe packaging of genetic information into chromatin regulates a wide range of vital processes that depend on direct access to the DNA template. Many chromatin-interacting complexes impact chromatin structure and their aberrant regulation or dysfunction has been implicated in various cancers and severe developmental disorders. A better understanding of the roles of chromatin-interacting complexes in such disease states requires a detailed mechanistic study. Many chromatin-interacting complexes modify chromatin structure, yet understanding the underlying mechanisms remains a major challenge in the field. Furthermore, how chromatin-interacting complexes are regulated to enable their various functions is incompletely understood. We will address these longstanding questions in two specific aims. Aim I: Building on our expertise in single-molecule biology, we will develop powerful single-molecule imaging approaches to monitor the action of chromatin-interacting complexes in real time. We will further probe how the diverse activities of the chromatin-associated complexes are coordinated and coupled to conformational transitions. Aim II: Drawing on our expertise in structural biology, we will use a range of structural techniques in combination with biochemical approaches to study the vital regulation of chromatin-interacting complexes by their regulatory subunits as well as by chromatin features. We expect to obtain ground-breaking insights into the mechanisms and regulation of disease-related chromatin-associated complexes, which may open up new horizons for developing therapeutic intervention strategies. Furthermore, the approaches developed here will enable the investigation of a large number of chromatin-related processes.

The packaging of genetic information into chromatin regulates a wide range of vital processes that depend on direct access to the DNA template. Many chromatin-interacting complexes impact chromatin structure and their aberrant regulation or dysfunction has been implicated in various cancers and severe developmental disorders. A better understanding of the roles of chromatin-interacting complexes in such disease states requires a detailed mechanistic study. Many chromatin-interacting complexes modify chromatin structure, yet understanding the underlying mechanisms remains a major challenge in the field. Furthermore, how chromatin-interacting complexes are regulated to enable their various functions is incompletely understood. We will address these longstanding questions in two specific aims. Aim I: Building on our expertise in single-molecule biology, we will develop powerful single-molecule imaging approaches to monitor the action of chromatin-interacting complexes in real time. We will further probe how the diverse activities of the chromatin-associated complexes are coordinated and coupled to conformational transitions. Aim II: Drawing on our expertise in structural biology, we will use a range of structural techniques in combination with biochemical approaches to study the vital regulation of chromatin-interacting complexes by their regulatory subunits as well as by chromatin features. We expect to obtain ground-breaking insights into the mechanisms and regulation of disease-related chromatin-associated complexes, which may open up new horizons for developing therapeutic intervention strategies. Furthermore, the approaches developed here will enable the investigation of a large number of chromatin-related processes.

Max ERC Funding

1 498 954 €

Duration

Start date: 2017-03-01, End date: 2022-02-28

Project acronymDII

ProjectThe Design of International Institutions: Legitimacy, Effectiveness and Distribution in Global Governance

Researcher (PI)Jonas Tallberg

Host Institution (HI)STOCKHOLMS UNIVERSITET

Call DetailsStarting Grant (StG), SH2, ERC-2007-StG

SummaryOne of the most profound trends in global governance over the past two decades is the growing extent to which international institutions offer mechanisms for the participation of transnational actors. This project will explore two central research questions, pertaining to the causes and effects of this shift in the design of international institutions: (1) Why have international institutions increasingly opened up to transnational actor involvement? (2) What are the consequences of involving transnational actors for the democratic legitimacy, problem-solving effectiveness, and distributional effects of international institutions? These are research questions that previously have not been explored systematically in existing literatures on international institutional design, transnational actors in global governance, and democracy beyond the nation-state. This project opens up a new research agenda on the design of international institutions through an ambitious combination of novel theory development and comparative empirical research. Theoretically, the project develops and tests alternative hypotheses about the causes and effects of transnational participation in international policy-making. Empirically, the project explores the dynamics of transnational participation through comparative case studies of five major international institutions, supplemented with a large-n mapping of formal mechanisms of transnational access in a broader sample of institutions. The project will help to establish an internationally competitive research group of post-doc researchers and Ph.D. students devoted to international institutional design, and consolidate the position of the principal investigator as a leading researcher in this field.

One of the most profound trends in global governance over the past two decades is the growing extent to which international institutions offer mechanisms for the participation of transnational actors. This project will explore two central research questions, pertaining to the causes and effects of this shift in the design of international institutions: (1) Why have international institutions increasingly opened up to transnational actor involvement? (2) What are the consequences of involving transnational actors for the democratic legitimacy, problem-solving effectiveness, and distributional effects of international institutions? These are research questions that previously have not been explored systematically in existing literatures on international institutional design, transnational actors in global governance, and democracy beyond the nation-state. This project opens up a new research agenda on the design of international institutions through an ambitious combination of novel theory development and comparative empirical research. Theoretically, the project develops and tests alternative hypotheses about the causes and effects of transnational participation in international policy-making. Empirically, the project explores the dynamics of transnational participation through comparative case studies of five major international institutions, supplemented with a large-n mapping of formal mechanisms of transnational access in a broader sample of institutions. The project will help to establish an internationally competitive research group of post-doc researchers and Ph.D. students devoted to international institutional design, and consolidate the position of the principal investigator as a leading researcher in this field.

Max ERC Funding

1 651 200 €

Duration

Start date: 2009-01-01, End date: 2014-12-31

Project acronymDisDyn

ProjectDistributed and Dynamic Graph Algorithms and Complexity

Researcher (PI)Danupon NA NONGKAI

Host Institution (HI)KUNGLIGA TEKNISKA HOEGSKOLAN

Call DetailsStarting Grant (StG), PE6, ERC-2016-STG

SummaryThis project aims to (i) resolve challenging graph problems in distributed and dynamic settings, with a focus on connectivity problems (such as computing edge connectivity and distances), and (ii) on the way develop a systematic approach to attack problems in these settings, by thoroughly exploring relevant algorithmic and complexity-theoretic landscapes. Tasks include
- building a hierarchy of intermediate computational models so that designing algorithms and proving lower bounds can be done in several intermediate steps,
- explaining the limits of algorithms by proving conditional lower bounds based on old and new reasonable conjectures, and
- connecting techniques in the two settings to generate new insights that are unlikely to emerge from the isolated viewpoint of a single field.
The project will take advantage from and contribute to the developments in many young fields in theoretical computer science, such as fine-grained complexity and sublinear algorithms. Resolving one of the connectivity problems will already be a groundbreaking result. However, given the approach, it is likely that one breakthrough will lead to many others.

This project aims to (i) resolve challenging graph problems in distributed and dynamic settings, with a focus on connectivity problems (such as computing edge connectivity and distances), and (ii) on the way develop a systematic approach to attack problems in these settings, by thoroughly exploring relevant algorithmic and complexity-theoretic landscapes. Tasks include
- building a hierarchy of intermediate computational models so that designing algorithms and proving lower bounds can be done in several intermediate steps,
- explaining the limits of algorithms by proving conditional lower bounds based on old and new reasonable conjectures, and
- connecting techniques in the two settings to generate new insights that are unlikely to emerge from the isolated viewpoint of a single field.
The project will take advantage from and contribute to the developments in many young fields in theoretical computer science, such as fine-grained complexity and sublinear algorithms. Resolving one of the connectivity problems will already be a groundbreaking result. However, given the approach, it is likely that one breakthrough will lead to many others.

SummaryThe long-term goal of our research is to advance the state-of-the-art in molecular simulation algorithms by 4-5 orders of magnitude, particularly in the context of the GROMACS software we are developing. This is an immense challenge, but with huge potential rewards: it will be an amazing virtual microscope for basic chemistry, polymer and material science research; it could help us understand the molecular basis of diseases such as Creutzfeldt-Jacob, and it would enable rational design rather than random screening for future drugs. To realize it, we will focus on four critical topics: • ALGORITHMS FOR SIMULATION ON GRAPHICS AND OTHER STREAMING PROCESSORS: Graphics cards and the test Intel 80-core chip are not only the most powerful processors available, but this type of streaming architectures will power many supercomputers in 3-5 years, and it is thus critical that we design new “streamable” MD algorithms. • MULTISCALE MODELING: We will develop virtual-site-based methods to bridge atomic and mesoscopic dynamics, QM/MM, and mixed explicit/implicit solvent models with water layers around macromolecules. • MULTI-LEVEL PARALLEL & DISTRIBUTED SIMULATION: Distributed computing provides virtually infinite computer power, but has been limited to small systems. We will address this by combining SMP parallelization and Markov State Models that partition phase space into transition/local dynamics to enable distributed simulation of arbitrary systems. • EFFICIENT FREE ENERGY CALCULATIONS: We will design algorithms for multi-conformational parallel sampling, implement Bennett Acceptance Ratios in Gromacs, correction terms for PME lattice sums, and combine standard force fields with polarization/multipoles, e.g. Amoeba. We have a very strong track record of converting methodological advances into applications, and the results will have impact on a wide range of fields from biomolecules and polymer science through material simulations and nanotechnology.

The long-term goal of our research is to advance the state-of-the-art in molecular simulation algorithms by 4-5 orders of magnitude, particularly in the context of the GROMACS software we are developing. This is an immense challenge, but with huge potential rewards: it will be an amazing virtual microscope for basic chemistry, polymer and material science research; it could help us understand the molecular basis of diseases such as Creutzfeldt-Jacob, and it would enable rational design rather than random screening for future drugs. To realize it, we will focus on four critical topics: • ALGORITHMS FOR SIMULATION ON GRAPHICS AND OTHER STREAMING PROCESSORS: Graphics cards and the test Intel 80-core chip are not only the most powerful processors available, but this type of streaming architectures will power many supercomputers in 3-5 years, and it is thus critical that we design new “streamable” MD algorithms. • MULTISCALE MODELING: We will develop virtual-site-based methods to bridge atomic and mesoscopic dynamics, QM/MM, and mixed explicit/implicit solvent models with water layers around macromolecules. • MULTI-LEVEL PARALLEL & DISTRIBUTED SIMULATION: Distributed computing provides virtually infinite computer power, but has been limited to small systems. We will address this by combining SMP parallelization and Markov State Models that partition phase space into transition/local dynamics to enable distributed simulation of arbitrary systems. • EFFICIENT FREE ENERGY CALCULATIONS: We will design algorithms for multi-conformational parallel sampling, implement Bennett Acceptance Ratios in Gromacs, correction terms for PME lattice sums, and combine standard force fields with polarization/multipoles, e.g. Amoeba. We have a very strong track record of converting methodological advances into applications, and the results will have impact on a wide range of fields from biomolecules and polymer science through material simulations and nanotechnology.

SummaryFateMapB aims to understand how the unique differentiation potential of fetal hematopoietic stem and progenitor cells
(HSPCs) contribute to functionally distinct cell types of the adult immune system. While most immune cells are replenished
by HSPCs through life, others emerge during a limited window in fetal life and sustain through self-renewal in situ. The
lineage identity of fetal HSPCs, and the extent of their contribution to the adult immune repertoire remain surprisingly
unclear. I previously identified the fetal specific RNA binding protein Lin28b as a post-transcriptional molecular switch
capable of inducing fetal-like hematopoiesis in adult bone marrow HSPCs (Yuan et al. Science, 2012). This discovery has
afforded me with unique perspectives on the formation of the mammalian immune system. The concept that the mature
immune system is a mosaic of fetal and adult derived cell types is addressed herein with an emphasis on the B cell lineage.
We will use two complementary lineage-tracing technologies to stratify the immune system as a function of developmental
time, generating fundamental insight into the division of labor between fetal and adult HSPCs that ultimately provides
effective host protection.
Aim 1. Determine the qualitative and quantitative contribution of fetal HSPCs to the mature immune repertoire in situ
through Cre recombination mediated lineage-tracing.
Aim 2. Resolve the disputed lineage relationship between fetal derived B1a cells and adult derived B2 cells by single cell
lineage-tracing using cellular barcoding in vivo.
Aim 3. Characterize the mechanism and effector functions of Lin28b induced B1a cell development for assessing the
clinical utility of inducible fetal-like lymphopoiesis.
The implications of FateMapB extend beyond normal development to immune regeneration and age-related features of
leukemogenesis. Finally, our combinatorial lineage-tracing approach enables dissection of cell fates with previously
unattainable resolution.

FateMapB aims to understand how the unique differentiation potential of fetal hematopoietic stem and progenitor cells
(HSPCs) contribute to functionally distinct cell types of the adult immune system. While most immune cells are replenished
by HSPCs through life, others emerge during a limited window in fetal life and sustain through self-renewal in situ. The
lineage identity of fetal HSPCs, and the extent of their contribution to the adult immune repertoire remain surprisingly
unclear. I previously identified the fetal specific RNA binding protein Lin28b as a post-transcriptional molecular switch
capable of inducing fetal-like hematopoiesis in adult bone marrow HSPCs (Yuan et al. Science, 2012). This discovery has
afforded me with unique perspectives on the formation of the mammalian immune system. The concept that the mature
immune system is a mosaic of fetal and adult derived cell types is addressed herein with an emphasis on the B cell lineage.
We will use two complementary lineage-tracing technologies to stratify the immune system as a function of developmental
time, generating fundamental insight into the division of labor between fetal and adult HSPCs that ultimately provides
effective host protection.
Aim 1. Determine the qualitative and quantitative contribution of fetal HSPCs to the mature immune repertoire in situ
through Cre recombination mediated lineage-tracing.
Aim 2. Resolve the disputed lineage relationship between fetal derived B1a cells and adult derived B2 cells by single cell
lineage-tracing using cellular barcoding in vivo.
Aim 3. Characterize the mechanism and effector functions of Lin28b induced B1a cell development for assessing the
clinical utility of inducible fetal-like lymphopoiesis.
The implications of FateMapB extend beyond normal development to immune regeneration and age-related features of
leukemogenesis. Finally, our combinatorial lineage-tracing approach enables dissection of cell fates with previously
unattainable resolution.